Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.
Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.
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DOI：
10.1002/aur.1529
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Powell CM
中科院分区：
文献类型：
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作者：
Jaramillo TC;Speed HE;Xuan Z;Reimers JM;Liu S;Powell CM
SHANK3是一种多结构域的突触支架蛋白，在兴奋性突触的突触后密度中组织蛋白质。临床研究表明，约0.5%的自闭症谱系障碍(ASD)病例可能与SHANK3突变/缺失有关。带有SHANK3突变的患者表现出认知缺陷，并伴有言语/语言延迟/受损以及重复和强迫/类强迫症(强迫症样)行为。为了研究SHANK3的突变/缺失如何改变导致ASD的大脑功能，我们独立地创造了缺失Shank3外显子4-9的小鼠，这是ASD患者中的一个区域。我们发现，外显子4-9(Shank3e4-9KO)的纯合缺失会导致Shank3的两个分子量最高的亚型丢失，而其他亚型的分子量显著减少。在行为上，Shank3e4-9杂合子(HET)和Shank3e4-9 KO小鼠都表现出重复梳理增加，新的和空间物体识别学习和记忆障碍，以及异常的超声波发声。Shank3e4-9KO小鼠在配对时也表现出异常的社会互动。对Shank3e4-9KO小鼠纹状体突触体组分的分析显示，Hmer 1b/c、GluA2和GluA3的表达降低。Shank3e4-9 HET和KO在纹状体中棘神经元兴奋性突触的NMDA/AMPA比值均显着降低。此外，尽管基线突触传递正常，Shank3e4-9KO小鼠显示出海马LTP降低。总之，这些行为、生化和生理变化表明，在自闭症的Shank3e4-9突变小鼠模型中，Shank3亚型在调节AMPAR亚基定位和NMDAR功能方面具有区域特异性的作用。
Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ~0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4–9, a region implicated in ASD patients. We find that homozygous deletion of exons 4–9 (Shank3e4–9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4–9 heterozygous (HET) and Shank3e4–9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4–9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4–9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4–9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4–9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4–9 mutant mouse model of autism.